The Genetic Landscape of Human Infertility: A Comprehensive Review
DOI:
https://doi.org/10.61919/m1t7mv21Keywords:
Infertility; Genetics; Azoospermia; Primary ovarian insufficiency; Polycystic ovary syndrome; Endometriosis; Epigenetics; Mitochondrial DNA; Preimplantation genetic testingAbstract
Background: Infertility affects approximately one in seven couples worldwide and arises from a heterogeneous interplay of chromosomal abnormalities, monogenic defects, polygenic susceptibility, epigenetic dysregulation, mitochondrial dysfunction, and environmental factors, yet a large proportion of cases still lack a clearly defined genetic etiology. Objective: To synthesize current evidence on the genetic, epigenetic, and mitochondrial determinants of male and female infertility, and to examine how these discoveries inform diagnostic evaluation, clinical management, and ethical, legal, and social frameworks. Methods: A narrative review of the literature was conducted using searches of major biomedical databases and targeted snowballing to identify original research, reviews, and professional guidelines on chromosomal, monogenic, polygenic, epigenetic, and mitochondrial mechanisms in human infertility, as well as their clinical translation into genetic testing, preimplantation genetic testing, and counseling. Results: Sex-chromosome aneuploidies, Y-chromosome microdeletions, and an expanding set of monogenic defects explain substantial fractions of severe male factor infertility and primary ovarian insufficiency, while GWAS have revealed complex polygenic architectures for polycystic ovary syndrome and endometriosis. Epigenetic and mitochondrial perturbations influence gamete competence and ART outcomes, and genetic testing and preimplantation genetic testing are increasingly embedded in guidelines, though access, variant interpretation, and ethical concerns remain challenging. Conclusion: The genetic landscape of human infertility is broad and rapidly evolving; integrating chromosomal, monogenic, polygenic, epigenetic, and mitochondrial insights into personalized reproductive care requires continued gene discovery, multi-ancestry research, robust counseling, and ethically grounded policy.
References
1. Sun H, Gong TT, Jiang YT, Zhang S, Zhao YH, Wu QJ. Global trends of infertility and childlessness: a systematic review and meta-analysis. Lancet Glob Health. 2019;7(1):e37-46.
2. Sang Q, Wang S, Liu Z, Li J, Zhang L, He L, et al. Understanding the genetics of human infertility. Science. 2023;380(6652):140-7.
3. Sharma M, Patel R, Singh K. Role of genetics, environmental, and lifestyle factors in male and female infertility. Fertil Sci Res. 2023;10(3):131-8.
4. Venkatesh SS, Ruth KS, Perry JRB. Genome-wide analyses identify infertility loci and relationships with reproductive traits. Nat Genet. 2025;57(5):789-801.
5. Krausz C, Riera-Escamilla A. Genetics of male infertility. Nat Rev Urol. 2018;15(6):369-84.
6. Skaletsky H, Kuroda-Kawaguchi T, Minx PJ, Cordum HS, Hillier L, Brown LG, et al. The male-specific region of the human Y chromosome is a mosaic of discrete sequence classes. Nature. 2003;423(6942):825-37.
7. Tüttelmann F, Simoni M, Kliesch S. Genetics of male infertility: current knowledge, clinical implications, and future directions. Andrology. 2017;5(4):603-12.
8. Tüttelmann F, Ruckert C, Röpke A. Disorders of spermatogenesis: perspectives for novel genetic diagnostics after 20 years of unchanged routine. Med Genet. 2018;30(1):12-20.
9. Krausz C, Hoefsloot L, Simoni M, Tüttelmann F; European Academy of Andrology; European Molecular Genetics Quality Network. EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions: state-of-the-art 2013. Andrology. 2014;2(1):5-19.
10. Krausz C, Casamonti E. Spermatogenic failure and the Y chromosome. Hum Genet. 2017;136(5):637-55.
11. Yang F, Silber S, Leu NA, Oates RD, Marszalek JD, Skaletsky H, et al. TEX11 is mutated in infertile men with azoospermia and regulates the progression of meiotic recombination and synapsis. Proc Natl Acad Sci U S A. 2015;112(34):E4687-94.
12. Yatsenko SA, Rajkovic A. Genetics of human female infertility. Biol Reprod. 2019;101(3):549-66.
13. Oud MS, Volozonoka L, Smits RM, Vissers LELM, Ramos L, Veltman JA. A systematic review and standardized clinical validity assessment of genes involved in male infertility. Hum Reprod. 2019;34(5):932-41.
14. Oud MS, Volozonoka L, Laan M. A systematic review of the validated monogenic causes of human male infertility: 2020 update. Hum Reprod Update. 2021;28(1):15-36.
15. Oates RD, Amos JA. The genetic basis of congenital bilateral absence of the vas deferens and cystic fibrosis. J Androl. 1994;15(1):1-8.
16. Bieniek JM, Lapin CD, Jarvi KA. Genetics of CFTR and male infertility. Transl Androl Urol. 2021;10(4):1391-400.
17. Yu J, Chen Z, Ni Y, Li Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systematic review and meta-analysis. Hum Reprod. 2012;27(1):25-35.
18. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015;21(6):787-808.
19. Jiao X, Ke H, Qin Y, Chen ZJ, Simpson JL. Genetic and genomic approaches to primary ovarian insufficiency. Trends Endocrinol Metab. 2018;29(7):400-12.
20. Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science. 2004;305(5687):1157-9.
21. Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet. 2007;81(5):1052-64.
22. Bouilly J, Bachelot A, Broutin I, Touraine P, Binart N. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort. Hum Mutat. 2011;32(10):1108-13.
23. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet. 2004;75(1):106-11.
24. Dixit H, Rao L, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N, et al. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet. 2006;119(4):408-15.
25. Aittomäki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959-68.
26. Laissue P, Christin-Maitre S, Touraine P, Kuttenn F, Ritvos O, Aittomäki K, et al. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol. 2006;154(5):739-44.
27. McAllister JM, Modi B, Miller BA, Biegler J, Bruggeman R, Legro RS, et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A. 2014;111(15):E1519-27.
28. Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14(12):e1007813.
29. Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017;8:15539.
30. Rahmioglu N, Macgregor S, Drong AW, Hedman ÅK, Harris HR, Randall JC, et al. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Hum Mol Genet. 2015;24(4):1185-99.
31. International Endometriosis Genetics Consortium, Sapkota Y, Steinthorsdottir V, Ferreira T, Laisk T, Kettunen J, et al. Shared genetics and causal relationships between endometriosis and a broad range of disease states. Hum Reprod. 2023;38(2):434-47.
32. Sato A, Hiura H, Okae H, Miyauchi N, Abe Y, Utsunomiya T, et al. Assessing loss of imprinting in sperm and its implications for assisted reproductive technology. Hum Mol Genet. 2019;28(3):466-75.
33. Rotondo JC, Lanzillotti C, Mazziotta C, Tognon M, Martini F. Epigenetics of male infertility: the role of DNA methylation. Front Cell Dev Biol. 2021;9:689624.
34. AlAzemi M, AlSairafi M, Bernard A, Koshy G, Omu AE. Perturbed follicular dynamics and hormone profiles in women with polycystic ovary syndrome. Clin Exp Obstet Gynecol. 2004;31(3):189-94.
35. Hiura H, Okae H, Miyauchi N, Sato F, Sato A, Van De Pette M, et al. Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies. Hum Reprod. 2012;27(8):2541-8.
36. Eroglu A, Layman LC. Role of ART in imprinting disorders. Semin Reprod Med. 2012;30(2):92-104.
37. Hattori H, Nakamura Y, Nakano Y, Kato Y, Sato B, Iwata H, et al. Mitochondrial DNA copy number in cumulus cells is a strong predictor of embryo implantation potential in IVF cycles. J Assist Reprod Genet. 2017;34(7):867-73.
38. Fragouli E, Spath K, Alfarawati S, Kaper F, Craig A, Michel CE, et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genet. 2015;11(6):e1005241.
39. Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010;465(7294):82-5.
40. Foresta C, Ferlin A, Gianaroli L, Dallapiccola B. Guidelines for the appropriate use of genetic tests in infertile couples. Eur J Hum Genet. 2002;10(8):471-81.
41. Patat O, Pagin A, Siegfried A, Mitchell V, Chassaing N, Faguer S, et al. Truncating mutations in the adhesion G protein-coupled receptor G2 gene ADGRG2 cause an X-linked congenital bilateral absence of vas deferens. Am J Hum Genet. 2016;99(2):437-42.
42. Fakhro KA, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores JL, Al-Shakaki A, et al. Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med. 2018;20(12):1615-26.
43. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for monogenic disease (PGT-M): a committee opinion. Fertil Steril. 2023;119(3):369-79.
44. Schlegel PN, Sigman M, Collura B, De Jonge CJ, Eisenberg ML, Lamb DJ, et al. Diagnosis and treatment of infertility in men: AUA/ASRM Guideline Part I. J Urol. 2021;205(1):36-43.
45. ESHRE Guideline Group on Female Fertility Preservation, Anderson RA, Amant F, Braat D, D'Angelo A, Chuva de Sousa Lopes SM, et al. ESHRE guideline: female fertility preservation. Hum Reprod Open. 2020;2020(4):hoaa052.
46. Goad J, Koenig BA, Biesecker BB, Ormond KE. Ethical, legal, and social implications of genetic testing in reproductive medicine. J Med Ethics. 2023;49(2):130-7.
47. Vega A, Blesa D. Gene-editing prospects in reproductive genetics: ethical, legal and social considerations. Nat Rev Genet. 2024;25(1):23-34.
48. ESHRE Task Force on Ethics and Law, Dondorp W, De Wert G, Pennings G, Shenfield F, Devroey P, et al. ESHRE Task Force on Ethics and Law 23: medically assisted reproduction in singles, lesbian and gay couples, and transsexual people. Hum Reprod. 2014;29(9):1859-65.
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Copyright (c) 2025 Asad Abdul Razzaq, Muhammad Sheryar Kamran, Tahira Batool, Asma Irshad, Rizwan Ali (Author)
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